title: Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin.
abstract: Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ruben
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Uemura
authors.forename: Mami
authors.initials: M
authors.lastname: Kamiya
authors.forename: Aiko
authors.initials: A
authors.lastname: Kiso
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okamoto
authors.forename: Yumi
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010654:Phenylbutyrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D015800:Protozoan Proteins; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; C521559:KNI 10006; D009842:Oligopeptides; D010654:Phenylbutyrates; D011480:Protease Inhibitors; D015800:Protozoan Proteins; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II